FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of tetrahydrofUran antifungals, in particular, posaconazole of formula I.
(Formula Removed)
The present invention further provides a process for the preparation of compound of formula II,
(Formula Removed)
a key intermediate in the preparation of posaconazole.
The present invention further provides novel intermediates useful for the preparation of posaconazole.
BACKGROUND OF THE INVENTION
Posaconazole of formula I, chemically known as (2R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(l,2,4-triazol-l-ylmethyl)-tetrahydrofuran-3-ylmethoxy]-phenyl]piperazin-1 -yljphenyl] -2-[ 1 (S)-ethyl-2(S)-hydroxypropyl] -3,4-dihydro-2H-1,2,4-triazol-3-one,
(Formula Removed)
is an antifungal agent which is used against a wide range of fungal pathogens, including both yeasts and molds.
U.S. Patent No. 5,661,151 (herein referred to as ' 151) discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole. The patent discloses several processes for the preparation of posaconazole.
According to one process, posaconazole is prepared by condensation of toluene-4-sulfonic acid (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[l,2,4]triazol-l-ylmethyl-tetrahydro-3-furan methyl ester with iV-protected triazolone derivative of following formula,
(Formula Removed)
wherein SEM is 2-(trimethyl)silylethoxymethyl group
in presence of a strong base in an aprotic solvent to give the compound of following formula,
(Formula Removed)
which is then deprotected using hydrochloric acid in methanol followed by N-alkylation with brosylated (2S,3R) alcohol of the following formula,
(Formula Removed)
wherein R represents hydroxyI protecting group (R = SEM, benzyloxymethyl),
in presence of strong base in an aprotic solvent to give hydroxy protected posaconazole which is then deprotected using hydrochloric acid in methanol to give posaconazole of formula I, which is purified by column chromatography.
In an alternative process, "151 discloses the preparation of posaconazole by condensing (3R-cis)-N-4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(lH-l,2,4-triazol-l-yl)methyl)-furan-3-yl]methoxy]-phenyl]-l-piperazinyl]-phenyl]-carbamic acid phenyl ester of following formula,
(Formula Removed)
with hydrazine hydrate in dioxane followed by cyclization in the presence of formamidine acetate in dimethylformamide to give a cyclized intermediate of following formula,
(Formula Removed)
which is further N-alkylated with brosylated (2S,3R) alcohol of formula,
(Formula Removed)
wherein R represents hydroxylprotecting group (R = SEM, benzyloxymethyl),
in presence of cesium carbonate in an aprotic solvent to give hydroxy protected posaconazole, and is then deprotected to give posaconazole.
The major drawback of the processes disclosed above is that JV-alkylation is carried out on cyclized triazolone intermediate which requires a large excess of expensive alkylating agent, and results in a mixture of 7V-alkylated and O-alkylated posaconazole, necessitating laborious purification methods such as column chromatography which is a time-consuming and tedious process; especially for large samples hence it is not suitable for large scale production and further results in low yields of posaconazole.
In a still another methodology, "151 discloses a process for preparing posaconazole by reacting (3R-cis)-N-4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(lH-l,2,4-triazol-l-yl)methyl)-furan-3-yl]methoxy]-phenyl]-l-piperazinyl]-phenyl]-carbamic acid phenyl ester with 2-[3-(2S, 3S)-2-(benzyloxy)pentyl]formic acid hydrazide in the presence of 1-8-diaza bicyclo [5.4.0]undec-7-ene under heating to give benzyl ether of posaconazole of formula,
(Formula Removed)
which on hydrogenolysis with palladium on carbon and formic acid in methanol affords posaconazole which is further purified on preparative thin layer chromatography.
U.S. Patent No. 5,625,064 ('064) discloses a process for the preparation of posaconazole which involves the condensation of compound of formula II,
with compound of following formula,
(Formula Removed)
wherein OB represents a suitable leaving group,
in the presence of base to give benzyl ether of posaconazole which is then deprotected either with palladium on carbon in the presence of formic acid or aqueous hydrobromic acid to form posaconazole. The starting compound of formula II is prepared by the method as depicted in the following scheme:
(Formula Removed)
wherein R represents H, CH3, C(fi$CH2
The above process suffers from several drawbacks such as low yields in the condensation step of phenyl carbamate intermediate and hydrazine derivative. We have observed that condensation of unprotected hydroxyl derivative with hydrazine derivative results in low yield of the compound of formula II due to less solubility of hydroxyl compound in most of the solvents. Further, condensation of O-benzyl protected phenyl carbamate derivative with hydrazine derivative results in formation of impurities which further requires tedious purification processes hence resulting in low yields. In our hands we have found that the dealkylation of

protected hydroxy group with aqueous hydrobromic acid does not goes to completion even after 30-35 hours and removal of unreacted starting material results in low yields
In view of the above, there is thus an obvious need to find an efficient and industrially advantageous process for the synthesis of posaconazole which overcomes the problems associated with the prior art such as long reaction time, low yields and tedious purifications.
OBJECT OF THE INVENTION
One principle object of the invention is to provide a process for the preparation of highly pure posaconazole in high yield and reduced time cycle.
Still another object of the present invention is to provide a process for the preparation of key intermediate of formula II in good yields using novel intermediates
Still another object of the present invention is to provide novel intermediates, process for the preparation thereof.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a process for the preparation of highly pure posaconazole of formula I
(Formula Removed)
from a compound of formula II.
(Formula Removed)
Another aspect of the present invention is to provide a process for the preparation of compound of formula II which comprises:
a. acylating 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol with a reagent of
formula R'C(O)X,
wherein R' represents straight, branched, substituted or unsubstituted Ci-C(, alky I or substituted or unsubstituted phenyl and X represents halogen,
to give a compound of formula III,
(Formula Removed)
b. reducing the compound of formula III using a noble metal catalyst, in an
organic solvent, under hydrogen gas pressure to give novel amine derivative
of formula IV,
(Formula Removed)
wherein R' is as defined above
c. condensing the compound of formula IV with substituted or unsubstituted
phenyl chloroformate in the presence of a tertiary amine base in a suitable
solvent to afford a novel and key intermediate of formula V,
(Formula Removed)
R' wherein R' is as defined above and R" is independently selected from the
group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl,
methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2,
CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, NO?, CHO, CH3CH(OH), acetyl, ethylene dioxy
d. reacting the compound of formula V with a hydrazine derivative of formula (Formula Removed)

( wherein Z is selected from -CHO; or -C(O)OC(CH3)3; or
(Formula Removed)
in the presence of tertiary amine base in an inert solvent to afford the compound of formula VII,
(Formula Removed)
wherein R' is as defined above
e. hydrolyzing the compound of formula VII using a base to afford the compound of formula II.
Still another aspect of the present invention is to provide novel intermediates of formulae III, IV, V and VII, preparation thereof and conversion thereof to posaconazole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides processes for the preparation of posaconazole of formula I.
(Formula Removed)
According to the one embodiment of the present invention, the posaconazole of formula I is prepared from a compound of formula II.
(Formula Removed)
The compound of formula II can be prepared by initially acetylating 4-[4-(4-nitro-phenyl)~piperazin-l-yl]-phenol with a reagent of formula R'C(O)X, wherein R' represents straight, branched, substituted or unsubstituted C\-C(, alkyl or substituted or unsubstituted phenyl and X represents halogen to give a novel compound of formula III,
(Formula Removed)
wherein R' represents straight, branched, substituted or unsubstituted C1-C6, alkyl or substituted or unsubstituted phenyl
which further represents a part of the invention. Although other suitable reagents capable of acylating such as inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester can equally be employed. Preferably acetyl chloride or acetic anhydride can be used. Acylation is carried out in the presence of tertiary amine base such as triethylamine in halogenated organic solvent such as dichloromethane at ambient temperature with stirring for a period of about 3-6 hours. Progress of the reaction can be monitored by HPLC or TLC. After completion of the reaction the solvent is removed by methods known in art like evaporation, distillation and the like to afford a compound of formula III.
The compound of formula III is further reduced using a noble metal catalyst, in an organic solvent, under hydrogen pressure to give novel amine derivative of formula IV,
(Formula Removed)
-wherein R' represents straight, branched, substituted or unsubstituted C1-C6, alkyl or substituted or unsubstituted phenyl
which further represents a part of the invention. Noble metal catalyst may be selected from platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. Hydrogen gas is applied at a pressure of about 1 kg/cm2 to about 3 kg/cm2. Organic solvent is selected from polar aprotic or polar protic solvent in combination with water; preferably a mixture of tetrahydrofuran and water is used. Reaction is preferably performed at ambient temperature.
In an alternate process, 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol is first reduced using a noble metal catalyst, in an organic solvent, under hydrogen pressure, and then it is acetylated to give compound of formula IV.
The compound of formula IV is further condensed with substituted or unsubstituted phenyl chloroformate in the presence of a tertiary amine base such as triethylamine in a suitable solvent to afford a novel and key intermediate of formula V,
(Formula Removed)
wherein R' represents straight, branched, substituted or unsubstituted C1-C6, alkyl or substituted or unsubstituted phenyl and R" is independently selected from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylenedioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, , NO2, CHO, CH3CH(OH), acetyl, ethylenedioxy;
Intermediate of formula V further represents a part of the invention. The condensation reaction is performed at a temperature of about 0 °C to about 10 °C.
Solvent can be selected from polar aprotic solvent, a non polar solvent or mixtures thereof, preferably N,N-dimethylformamide, toluene or mixture thereof is used.
In an alternate process, compound of formula V can also be prepared by the condensation of 4-[4-(4-amino-phenyl)-piperazin-l-yl]-phenol with substituted or unsubstituted phenyl chloroformate derivative followed by acylation with a reagent of formula R'C(O)X.
Thereafter compound of formula V is converted to compound of formula II thorough novel intermediate of formula VII. Typically, the compound of formula V is condensed with hydrazine derivative of general formula VI,

(Formula Removed)
wherein Z is selected from a group consisting of —CHO; -C(O)OC(CH3)3; -
C(O)OCH2C(tf5
in the presence of tertiary amine base in an inert solvent to afford the novel and
key intermediate of formula VII,
(Formula Removed)
wherein R' is as defined above,
which further represents a part of the invention. Preferably, compound of formula V and hydrazine derivative of formula VI is suspended in an inert solvent in the presence of a suitable base. Base can be selected from tertiary amine base such as triethylamine. Solvent can be selected from 1,2-dimethoxyethane, diethyl ether or tetrahydrofuran preferably 1,2-dimethoxyethane. The resulting suspension is refluxed at about 60 °C to about 100 °C for a period of 20-30 hours then an aromatic hydrocarbon solvent such as hexane, toluene or xylene is added preferably toluene is added. The resulting suspension is further refluxed at about 90 °C to about 120 °C for a period of 20-30 hours preferably till reaction
completion. The product is isolated preferably by distillation of the solvent to give compound of formula VII in high yield and purity.
It is advantageous to use O-acylated derivative of formula V during condensation with hydrazine derivative as the solubility of O-acylated compound of formula V is better in most of the solvent as compared to the O-alkylated phenyl carbamte derivatives as disclosed in the prior art and hence results in better yields. Further, hydrolysis of 0-acylated compound can be carried out under mild reaction conditions.
The compound of formula VII is further hydrolyzed to compound of formula II using suitable base. The process comprises of dissolving the compound of formula VII in a suitable alcoholic solvent selected from C1-C4 alcohols, preferably methanol, ethanol, propanol, n-butanol, isopropanol or tertiary butanol and the like. The reaction mass is then treated with an aqueous solution of alkali metal hydroxide base preferably sodium hydroxide at a temperature of below 15 °C for time sufficient to convert to compound of formula II. The resulting mixture is then neutralized with aqueous acidic solution preferably with IN hydrochloric acid solution. The compound of formula II is then extracted with halogenated hydrocarbon solvent such as dichloromethane by layer separation method. The compound of formula II is finally crystallized in ethereal solvent preferably in methyl tert-butyl ether in high yield and purity. The compound of formula II is further converted into posaconazole by the processes known in prior art or as disclosed in present invention.
Generically, the compound of formula II is debenzylated to a compound of formula VIII,
(Formula Removed)
and thereafter the resulting debenzylated compound of formula VIII is condensed with compound of formula IX to afford posaconazole of formula I.
(Formula Removed)
Typically, debenzylation of the compound of formula II is carried out using mineral acid in an organic solvent, in the presence of a noble metal catalyst employing hydrogen gas pressure. Generally, hydrogen is applied at a pressure of about 2 kg/cm to 8 kg/cm . Preferably, the hydrogen pressure applied is about 3 kg/cm2 to 6 kg/cm2.
Mineral acid can be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, preferably hydrochloric acid. Organic solvent may be selected from alcoholic solvent such as C1-C4 alcohols, dimethylformamide, dimethyl sulfoxide, preferably methanol, ethanol, propanol, n-butanol, isopropanol, dimethyl sulfoxide and more preferably methanol is employed. Noble metal catalyst may be selected from Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. The debenzylation reaction is usually conducted at a temperature of about 20 °C to 80 °C. Preferably, the temperature is maintained during reaction is about 40 °C to about 60 °C for a period of about 1 to 5 hours. The completion of reaction may be monitored by TLC or HPLC. After completion of reaction, reaction mixture is filtered to remove the catalyst. Solvent is distilled out and the resulting residue is further dissolved in suitable aliphatic esters such as ethyl acetate and further stirred for 1 to 2 hours at the reflux temperature of the solvent to afford debenzylated compound of formula VIII.
Thereafter, the resulting debenzylated compound of formula VIII is condensed with compound of formula IX in the presence of a base in an organic solvent, at temperature of about 30 °C to the reflux temperature of the solvent to afford posaconazole of formula I.
Base can be selected from an alkali or alkaline earth metal hydroxide, hydrides or carbonates, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydride, lithium hydride, potassium hydride and the like, sodium carbonate, potassium carbonate, calcium carbonate, and the like. Organic solvent can be selected from polar aprotic or protic solvent preferably methanol, ethanol, isopropanol, dimethylformamide, dimethyl sulfoxide, and the like or mixture thereof.
Preferably the condensation reaction is carried out in the presence of sodium hydroxide in a suitable solvent selected from isopropyl alcohol or dimethyl sulfoxide at a temperature of about 30 °C to 80 °C. Normally, the condensation reaction is completed in about 3 to 15 hours. To the resulting solution, water is added with stirring for a period of 1-2 hours. The reaction mass is then filtered to obtain to afford posaconazole of formula I.
Posaconazole can further be purified by recrystallization using the solvent selected from C1-C4 linear or branched alcoholic solvents such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol, acetonitrile, acetone, water and mixtures thereof, preferably methanol.
Wherever required the intermediates and final compound posaconazole can be treated with activated charcoal or silica gel to improve the color and quality of the material. Isolation and purification of the compounds and intermediates described can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
EXAMPLES
Example 1: Preparation of posaconazole
Step a) Preparation of acetic acid 4-f4-(4-nitro-phenyl)-piperazin-l-vll-phenyl ester
To a stirred suspension of 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol (50g), triethylamine (34.34g) in dichloromethane (500ml), acetyl chloride (16.0g) was added slowly at 10oC The temperature of the resulting mixture was raised to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC), the reaction mixture was washed with water (250ml) and brine (250ml). Organic layer was separated and evaporated to obtain 50g of title compound having purity of 98.0% by HPLC.
Step b) Preparation of acetic acid 4-[4-(4-amino-phenvl)-piperazin-l-yl]-phenyl ester
A stirred suspension of acetic acid 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenyl ester (50g) in tetrahydrofuran (1500ml) and water (50ml) was hydrogenated for 1-2 hours under a hydrogen pressure of 2 kg/cm at ambient temperature in the presence of palladium on carbon (5%, 5.0g). After completion of hydro genation (monitored by TLC), the catalyst was filtered off and solvent was evaporated to obtain 43g of the title compound having purity of 98.0% by HPLC.
Step c) Preparation of 2-(2(SVbenzvIoxv-l(SVethvl-propyl)-4-{4-[4-(4-hvdroxy-phenvl)-piperazin-l-vll-phenvl}-2.4-dihvdro-[l,2,41triazol-3-one
To a stirred mixture of acetic acid 4-[4-(4-amino-phenyl)-piperazin-l-yl]-phenyl ester (43g), triethylamine (28g) in toluene (860ml) and N,N-dimethylformamide (86ml), phenyl chloroformate (26g) was added at 0 °C-10 °C. The resulting mixture was warmed to ambient temperature and stirred for 5-6 hours. To the resulting mixture 2-[3-(2S, 3S)-2-(benzyloxy)pentyl]formic acid hydrazide (43g) was added and further stirred for 24-30 hours at 80 °C-100 °C. After completion of reaction (monitored by TLC), solvent was distilled and residue was dissolved in methanol (430ml). The solution was cooled to 0 °C-10 °C. The pH of the cooled solution was adjusted to 8-9 with aqueous sodium hydroxide (10%w/v)
and further stirred for 30 minutes. The pH of the resulting mixture was again adjusted to 6-7 with hydrochloric acid (1N) and the product was extracted with dichloromethane (2x400ml). The organic layer was separated and subsequently washed with saturated solution of sodium bicarbonate (400ml) and brine (400ml). The organic layer was treated with activated charcoal, solvent was distilled off and the title compound was crystallized in methyl tert-butyl ether to obtain 64.0g of the title compound having purity of 97.0% by HPLC.
Step d) Preparation of 2-(1(S)-ethvl-2(S)-hydroxv-propvn-4-{4-r4-(4-hvdroxv-phenvI)-piperazin-l-yn-phenyl}-2,4-dihvdro-[l,2,41triazol-3-one
2-(2(S)-Benzyloxy-1 (S)-ethyl-propyl)-4- {4-[4-(4-hydroxy-phenyl)-piperazin-1 -yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one (30g) was taken in 5N hydrochloric acid (60 ml) in methanol (300ml), and was hydrogenated for 2-3 hours under a hydrogen pressure of 4 kg/cm at 50 °C in the presence of palladium on carbon (10%, 3g). After completion of hydrogenation (monitored by TLC), the catalyst was filtered off and washed with methanol (60 ml). The combined filtrate was concentrated to obtain residue. Residue was dissolved in ethyl acetate (600ml) and refluxed for 1 hour. The resulting mixture was cooled and filtered to obtain 26g of the title compound as a white solid having purity of 98.0% by HPLC.
Step e) Preparation of posaconazole
To a stirred solution of 2-(l(S)-ethyl-2(S)-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one obtained above in dimethyl sulfoxide (140ml), a solution of sodium hydroxide (5.15g) in water was added at ambient temperature and stirred for 15 minutes. The reaction mixture was cooled to 10 °C and (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[(lH-l,2,4-triazole-l-yl)methyl]-tetrahyro-3-furanmethanol-4-chlorobenzenesulphonate (30.0 g) was added. The temperature of the read. on mass was raised to 35-40 °C with stirring for 10-12 hours. To the resulting solution, water was added drop wise and further stirred for 60 minutes. The resulting mixture was filtered to obtain 36.4 g of the crude title compound as a white solid having purity of 97.0% by HPLC.
Purification
The crude posaconazole (36.4g) was taken in methanol (360ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (50ml) and dried at 50 °C to obtain 32g of the title compound having purity of 99.5% by HPLC.
Example 2; Preparation of acetic acid 4-f4-(4-phenoxycarbonylamino-phenyl)-piperazin-1-yll-phenyl ester
Method A:
To a solution of 4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl-carbamic acid phenyl ester (40g) and triethylamine (41g) in N,N-dimethylformamide (400ml), acetylchloride (24.2g) was added at 0 °C-10 °C. The resulting mixture was warmed to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC), the reaction mixture was quenched with ice water (1200ml) and filtered to obtain 42.Og of the title compound having purity of 98.0% by HPLC.
Method B:
To a suspension of acetic acid 4-[4-(4-amino-phenyl)-piperazin-l-yl]-phenyl ester (5g), triethylamine (3.2g) in toluene (100ml) and N,N-dimethylformamide (10ml), phenyl chloroformate (2.52g) was added at 10 °C. The resulting mixture was stirred for 6-8 hours at same temperature and filtered to obtain 6.5g of the title compound having purity of 95.0% by HPLC.
Example 3: Preparation of 2-(2(S)-benzyloxy-l(S)-ethvl-propyl)-4-{4-[4-(4-hydroxy-phenvl)-piperazin-l-yll-phenyl}-2,4-dihydro-[l,2,41triazol-3-one.
To a stirred suspension of acetic acid 4-[4-(4-phenoxycarbonylamino-phenyl)-piperazin-1-yl]-phenyl ester (20g) in 1,2-dimethoxyethane (300ml), 2-[3-(2S,3S)-2-(benzyloxy)pentyl] formic acid hydrazide (14.7g) and triethylamine (5g) were added at ambient temperature. The resulting suspension was heated to 80 °C and stirred for 24 hours. To the resulting mixture toluene (300ml) was added and
stirred for a period of 24 hours at 100 °C-110 °C. After completion of reaction (monitored by TLC), solvent was removed by distillation and the resulting residue was dissolved in methanol (200ml) and the solution was cooled to 0 °C-10 °C. The pH of the cooled solution was adjusted to 9-10 with aqueous sodium hydroxide (10% w/v) and further stirred. The pH of the resulting mixture was again adjusted to 6-7 with 1N solution of hydrochloric acid and product was extracted with dichloromethane (2x400ml). The organic layer was separated and subsequently washed with saturated solution of sodium bicarbonate (300ml) and brine (300ml). The organic layer was treated with activated charcoal, distilled and the title compound is crystallized in methyl tert-butyl ether to obtain 22g of the title compound having purity of 98.0% by HPLC.
Example 4: Preparation of posaconazole
a) Preparation of 2-(l(S)-ethvl-2(S)-hydroxv-propvl)-4-{4-[4-(4-hydroxv-
phenyI)-piperazin-l-yIl-phenvl}-2,4-dihydro-[l,2,4|triazoI-3-one
2-(2(S)-benzyloxy-1 (S)-ethyl-propyl)-4- {4-[4-(4-hydroxy-phenyl)-piperazin-1 -yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one (6.5g) was taken in 5N hydrochloric acid (13ml) in methanol (65ml) and was hydrogenated for 2-3 hours under a hydrogen gas pressure of 4 kg/cm at 50 °C in the presence of palladium on carbon (10%, 0.65g). After completion of reaction (monitored by TLC), the catalyst was filtered off and washed with methanol (15ml). The combined filtrate was concentrated to obtain a residue. Residue was dissolved in ethyl acetate (65ml) and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 5.3g of the title compound as a white solid having purity of 98.0% by HPLC.
b) Preparation of posaconazole
To a stirred solution of step (a) product (5g) in isopropyl alcohol (50ml), a solution of sodium hydroxide (1.44g) in water was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[(lH-l,2,4-triazole-l-yl)methyl]-tetrahyro-3-furanmethanol-4-chloro-benzene sulphonate (6.5g) was added, raising the temperature to 70-80 °C and
stirred at the same temperature for 6-7 hours. The resulting mixture was cooled, filtered to obtain 7.5g of the title compound as a white solid having purity of 97.0%byHPLC. '
Purification
The crude posaconazole (7.5g) was taken in methanol (75ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (15ml) and dried at 50 °C to obtain 6g of the title compound having purity of 99.5% by HPLC.

WE CLAIM
1. A process for the preparation of posaconazole of formula I
(Formula Removed)
which comprises:
a. acylating 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol with a with a reagent of formula R'C(O)X,
wherein R' represents straight, branched, substituted or unsubstituted Cj-C6 alkyI or substituted or unsubstituted phenyl and X represents halogen,
to give a compound of formula III,
(Formula Removed)
b. reducing the compound of formula III using a noble metal catalyst in an organic solvent, under hydrogen pressure to give amine derivative of formula IV.
(Formula Removed)
wherein R' is as defined above
c. condensing the compound of formula IV with substituted or unsubstituted phenyl chloro,formate in the presence of a tertiary amine base in a suitable solvent to afford key intermediate of formula V,
(Formula Removed)
wherein R' is as defined above and R " is independently selected from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, NO2, CHO, CHiCH(OH), acetyl, ethylene dioxy
d. reacting the compound of formula V with a compound of formula VI,
(Formula Removed)
wherein Z is selected from -CHO; or -C(O)OC(CH3)3; or -C(O)OCH2C6H5
in the presence of tertiary amine base in an inert solvent to afford the compound of formula VII,
(Formula Removed)
wherein R' is as defined above
e. hydrolyzing the compound of formula VII with a base to afford the
compound of formula II and
(Formula Removed)
f. converting the compound of formula II to posaconazole of formula I.
2. The process according to claim 1, wherein in step b), noble metal catalyst is selected from platinum, palladium-carbon, ruthenium-carbon, rhodium-carbon; and solvent is selected from polar aprotic or polar protic solvent in combination with water.
3. The process according to claim 1, wherein in step c) solvent is selected from polar aprotic solvent or non polar solvent like A^A^dimethylformamide, toluene or mixture thereof.
4. The process according to claim 1, wherein in step d) solvent is selected from 2-dimethoxyethane, diethyl ether or tetrahydrofuran.
5. A process for the preparation of a compound of formula II,
(Formula Removed)
which comprises:
a. acetylating 4- [4-(4-nitro-phenyl)-piperazin-l-yl] -phenol with a reagent of formula R'C(O)X,
wherein R' represents straight, branched, substituted or unsubstituted Cj-C6 alkyI or substituted or unsubstituted phenyl and X represents halogen,
to give compound of formula III,
(Formula Removed)
wherein R' is as defined above.
b. reducing compound of formula III using a noble metal catalyst in an organic solvent, under hydrogen pressure to give amine derivative of formula IV.
(Formula Removed)
wherein R' is as defined above
c. condensing compound of formula IV with substituted or unsubstituted
phenyl chloroformate in the presence of a tertiary amine base such as
triethylamine in a suitable solvent to afford a novel and key intermediate
of formula V,
(Formula Removed)
wherein R' is as defined above and R" is independently selected from the group consisting ofH, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy
d. reacting the compound of formula V with a compound of formula VI,
(Formula Removed)
wherein Z is selected from —CHO; or -C(O)OC(CH3)3, or C(O)OCH2C6H5
in the presence of tertiary amine base in an inert solvent to afford the compound of formula VII,
(Formula Removed)
wherein R' is as defined above
e. hydrolyzing the compound of formula VII using a base to afford the compound of formula II.
6. The process according to claim 5, wherein in step b) noble metal catalyst is selected from platinum, palladium, rhodium, ruthenium; solvent is selected from polar aprotic or polar protic solvent in combination with water; and in step c) inert solvent is selected from polar aprotic solvent, a non polar solvent like N,N-dimethylformamide, toluene or mixture thereof.
7. The process according to claim 5, wherein in step d) solvent is selected from 2-dimethoxyethane, diethyl ether or tetrahydrofuran and in step e) base is alkali metal hydroxide.
8. A compound of formula IV
(Formula Removed)
wherein R' represents straight, branched, substituted or unsubstituted Ci-C^ alkyl or substituted or unsubstituted phenyl
9. A compound of formula V
(Formula Removed)
wherein R' represents straight, branched, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted phenyl and R" is independently selected
from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy, N(CH3)2, phenyl, phenoxy, benzyl, benzyloxy, NO2, CHO, CH3CH(OH), acetyl, ethylene dioxy
10. A compound of formula VII
(Formula Removed)
wherein R' represents straight, branched, substituted or unsubstituted C1-C6, alkyl or substituted or unsubstituted phenyl